DESCRIPTION: The broad goal of this competing renewal is to further elucidate the relative roles of the nonsteroidal factors, inhibin B and follistatin (FS), gonadal sex steroids, and GnRH in the control of FSH secretion in the human male. SA #1, to define the role of non-steroidal factors (inhibin B and FS) relative to sex steroids in the feedback control of FSH secretion in the human male, will be pursued in studies of normal and GnRH deficient men (ON pulsatile GnRH). Subjects will be studied: in the baseline state, b)following suppression of SS by ketoconazole, and c) during physiologic replacement of testosterone (T), estradiol (E2), T+E2, T+ an aromatase inhibitor (AI). Inhibin B and FS will be monitored along with FSH, LH, FAS (free alpha subunit), T and E2. Agonadal men will provide the references ranges for FSH levels and GnRH frequency, with and without steroids. The hypotheses are: 1) gonadal non-=SS factors account for a significant proportion of the negative feedback of FSH; 2) inhibin B is predominant among these, and 3) follistatin in the peripheral circulation is of pituitary origin. Specific Aim 2 is to establish the relative contributions of T & E2 to FSH feedback, and will be pursued by comparing FSH in response to T vs T+AI. The hypothesis is that E2 is the predominant SS negative feedback regulator of FSH. Specific Aim 3, to examine the interactions between GnRH, SS & Non-steroidal feedback in the control of FSH, will be pursued by comparing the FSH response to SS ablation in GnRH deficient men maintained at an intact GnRH dose and frequency (q2hr) vs. in those switched to a castrate regimen. The hypothesis is that GnRH input has a significant on FSH when SS and/or inhibin B levels are low. Detailed parallel studies undertaken in normal, GnRH deficient, and agonadal males will thus provide new insights into the physiology of FSH regulation in the human which will be the cornerstone for subsequent studies of the pathophysiology of men with reproductive disorders.